Project Inform - March, 1997

Updates from Previously Reported Studies

Results continue to be encouraging from the Merck 035 study. The study enrolled people with CD4+ cell counts ranging from 50 to 400 who had used prior AZT therapy. They received AZT + 3TC, indinavir alone or AZT + 3TC + indinavir. The results for people receiving the 3-drug combination are shown in Table 1:

N/D=Not Determined at this time.

Five people receiving the 3-drug combination had lymph node biopsies to look for viral RNA. Two had fewer than 20 copies of HIV RNA and were HIV antibody negative in peripheral blood and lymph node cultures. But 50-100 copies of HIV RNA were detected in the lymph nodes of two others. This measure, however, remains "below the limit of detection" used in most other studies.

Ritonavir + Saquinavir: Similarly, results from a study comparing different doses of ritonavir and saquinavir continue to indicate that this combination may be an option for people who have cycled through the nucleoside analogues. The study enrolled 141 people with CD4+ cell counts between 100 and 500, who had not been on previous protease inhibitor therapy. The results after 24 weeks (20 week results in parentheses) are shown in Table 2:

VL=Viral Load ( )=data at 20 weeks
LD=Limit of detection, 500 copies RNA
* =2x daily ** =3x daily

New Drugs and Combinations

DMP-266 + Indinavir: Some encouraging results have been reported on the use of DMP-266 (a non-nucleoside reverse transcriptase inhibitor, or NNRTI) in combination with indinavir (Crixivan). The thirty participants had CD4+ cell counts between 100-500 and HIV RNA levels above 20,000 who had been either previously treated with nucleoside analogue therapy or were naïve to this form of therapy. All received indinavir alone for two weeks and were then assigned to receive either DMP-266 + indinavir or continue on indinavir alone. The laboratory used a very sensitive viral load test that measured down to zero copies of HIV RNA, creating an opportunity for a larger "log reduction" than is reported in most other studies. Therefore, the results were reported in two ways. When the viral load reductions were based on the values reported by the laboratory, people using the combination had a 4.1 log drop after 24 weeks compared to a 2.2 log drop for those on indinavir alone. The other analysis described anyone whose viral load fell below 400 copies of HIV RNA as having an average of 200 copies. This more conservative method reported people using the combination as having a 2.4 log drop after 24 weeks compared to 1.5 log drop for those on indinavir alone. At 24 weeks, 82% of the 21 people on the combination had fewer than 400 copies of HIV RNA compared to 38% of the 9 people using indinavir alone. Both groups had about 100 CD4+ cell increases after 24 weeks. Side effects were mild to moderate, including headache, rash and diarrhea. Using either analysis, this is very impressive data, roughly equal to the best data seen from most 3-drug combinations.

1592U89: Results with 1592U89, Glaxo Wellcome’s nucleoside analogue, continue to show promise. People received 1 of 4 dose regimens of 1592 (200 mg 3x daily, 300 mg 2x daily, 400 mg 3x daily or 600 mg 3x daily). After 4 weeks of receiving 1592 alone, people either continued 1592 alone or added AZT for 8 more weeks. At the end of the initial 4 weeks, people had a 1.5 to 2.2 log drop in HIV RNA and an increase of 79 to 127 CD4+ cells. There were no significant differences between the dose groups, perhaps due to the small number of people using each dose. After 12 weeks, 22% of those using 1592 alone had viral load below the limit of detection (fewer than 400 copies of HIV RNA) compared to 64% of those using the combination. About 60% of the people who received 1592 alone for 12 weeks developed a mutation that may confer resistance to 1592. Only 13% of those on AZT + 1592 developed such a mutation. One interesting observation was that when people with a 1592-associated resistant mutation stopped taking 1592, the mutation disappeared. Whether the resistant mutation is truly "gone" or simply much harder to detect is unclear.

141W94: Some preliminary results show potent antiviral activity from the combination of 141W94 (the Glaxo Wellcome/Vertex protease inhibitor also known as VX 478) and the new Glaxo Wellcome nucleoside analogue drug 1592. After 4 weeks, the maximum median viral load drop was 2.1 logs and 71% of the participants had a viral load below the limit of detection (fewer than 400 copies of HIV RNA). Additionally, a 60 to 125 CD4+ cell increase was observed. Two factors making the results more impressive than they might sound are that no one knows the ideal dose of either drug, and in most similar studies, the maximum drop in viral load isn’t seen until 16-24 weeks.

MKC 422: Triangle Pharmaceuticals’ MKC 422, a new nucleoside analogue compound shows good activity. MKC 422 behaves like a non-nucleoside reverse transcriptase inhibitor. Participants on low doses had only a slight drop in HIV RNA levels, which soon rebounded. The highest dose group studied received 500 mg once a day, still a modest dose level compared to most drugs. Participants in this dose group had a maximum 1 log drop in HIV RNA, which is quite impressive given that it was used as a single agent and no one really yet knows what the ideal dose will be. There has been no significant impact on CD4+ cell numbers seen to date. Higher doses of the drug are still being studied.

Hydroxyurea: A study conducted in Switzerland enrolled 142 people with CD4+ counts between 200 and 500 who received ddI + d4T or ddI + d4T + hydroxyurea. Most of the participants had received no previous antiretroviral therapy. Results after 12 weeks are shown in Table 3:

VL=Viral Load
LD=Limit of detection,500 copies HIV RNA

Researchers believe that the modest CD4+ cell count increase among people receiving the triple combination is due to the hydroxyurea, which can cause temporary, reversible suppression of lymphocyte production. The impact of the lower CD4+ cell count increases is not known but hydroxyurea may still represent an option for lowering viral load when other approaches fail.

d4T + 3TC: A French study, known as ALTIS, showed that d4T + 3TC may be a very powerful combination and may be useful as part of a 3-drug combination. ALTIS 1 enrolled 42 people who had not been on any prior antiretroviral therapy, while ALTIS 2 enrolled 41 people with prior AZT, ddI and ddC experience but who had never used d4T and 3TC. If participants still had viral load above 3,000 HIV RNA copies after six months, ritonavir was added to their combination. Otherwise, they continued on the d4T + 3TC combination. Results are shown in Table 4:

VL=Viral Load
LD=Limit of detection, 200 copies HIV RNA

d4T + 3TC did not show the rebound in viral load seen in studies of AZT + 3TC. In ALTIS 1 baseline viral load was the only factor that correlated with response (viral load and CD4+ cell counts). In ALTIS 2, people who had only used single drug therapy fared better than those who had used multiple drugs and combinations. These data suggest that d4T + 3TC is at least as active as AZT + 3TC; good news for people who cannot or do not wish to use AZT. However, most researchers still believe that it makes more sense to initiate therapy with a 3-drug combination, which includes a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. This is because none of the 2-drug nucleoside combinations seems able to reduce viral load below the limit of detection in most users. When such a combination routinely fails to reach this level of suppression, it is bound to fail over time due to the development of resistance, thus wasting the two drugs for only a short-term, limited benefit. However, when the two drugs are used in 3-drug combinations with a potent protease inhibitor most users see their virus levels fall below the limit of detection, which better protects all three drugs against resistance.

Preliminary results from the AIDS Clinical Trials Group (ACTG) study 193A show that 3-drug combination therapy was better than 2-drug combinations or alternating therapy in delaying disease progression and prolonging survival. One thousand three hundred and fourteen people with fewer than 50 CD4+ cells took part. They received AZT alternating with ddI, AZT + ddC, AZT + ddI or AZT + ddI + nevirapine (Viramune). Results are shown in Table 5:

The triple combination was superior to the alternating regimen and AZT + ddC in delaying disease progression and prolonging survival. There was no significant difference between the triple combination and the group that received AZT + ddI.

Advanced Disease Studies: A small pilot study conducted in Canada reported encouraging news for people who have been on extensive combination antiretroviral therapy. Twenty-one people with fewer than 50 CD4+ cells, who had been on combination therapy received indinavir + nevirapine + 3TC. After 20 weeks on this 3-drug combination, people had an average 3 log reduction in viral load, 100 CD4+ cell increase and 400 CD8+ cell increase. Perhaps even more encouraging, 60% of the participants had viral load reductions below the limit of detection (fewer than 500 copies of HIV RNA). Fifteen percent had viral load reductions below detection even by the ultra sensitive PCR (polymerase chain reaction test) which measures down to 20 copies of HIV RNA.

Two other studies showed encouraging data for people with advanced disease. The first enrolled 32 people with fewer than 250 CD4+ cells, who had viral loads greater than 5,000 copies or evidence of disease progression despite 4 months of 3-drug therapy (2 nucleoside analogues and a protease inhibitor). They received ritonavir (600 mg twice daily) + saquinavir (400 mg twice daily) + two nucleoside analogues. The results are shown in Table 6:

VL=Viral Load
LD=Limit of detection, 400 copies HIV RNA

The second study offered more encouraging news. Three hundred and twenty people with fewer than 50 CD4+ cells (the average was 17 CD4+ cells) and who had been on prior nucleoside analogue therapy (except 3TC) received AZT + 3TC, indinavir alone or AZT + 3TC + indinavir. The results after 24 weeks of study are shown in Table 7:

VL=Viral Load
LD=Limit of detection,500 copies HIV RNA

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The original of this article can be found at http://www.projinf.org/pub/21/AntiviralUpdate.html